Carbon monoxide (CO) is, by common definition, a colourless, odourless, tasteless, non-corrosive gas of about the same density as that of air and is the most commonly encountered and pervasive poison in our environment. Depending on the extent and time of exposure, CO is capable of producing a myriad of debilitating and harmful residual effects to the organism (1). The most immediate of these effects, and perhaps the most notorious one, is binding to hemoglobin in the blood stream, which rapidly decreases the oxygen transport capability of the cardiovascular system.
Paradoxically, more than half a century ago it was found that CO is constantly formed in humans in small quantities (2), and that under certain pathophysiological conditions this endogenous production of CO may be considerably increased (3-5). The discovery that hemoglobin, a heme-dependent protein, is required as substrate for the production of CO in vivo (6,7) and the identification of the enzyme heme oxygenase as the crucial pathway for the generation of this gaseous molecule in mammals (8) set the basis for the early investigation of an unexpected and still unrecognized role of CO in the vasculature (9).
A discussion of the background studies carried out in this area are reported in the publication WO 02/092075, which originates from the work of some of the present inventors. The beneficial physiological effects of carbon monoxide (CO) has also been recognized and reported in a number of other publications. As a consequence of these beneficial physiological effects, the literature contains many proposals and studies for providing methods or compounds that have use in delivering therapeutic quantities of carbon monoxide at an appropriate rate to a desired physiological site.
WO 2003/000114 (Beth Israel Deaconess Medical Center) describes a method involving the administration of a carbon monoxide-oxygen (O2) gaseous mixture to an organ, which helps to prevent organ damage for transplant procedures.
Similarly, WO 03/094932 (Yale University) discloses several methods for the generation of carbon monoxide gas and the subsequent administration of the gas to a patient for the treatment of various disorders.
WO 02/078684 (Sangstat Medical Corporation) discloses methods and pharmaceutical compositions for the treatment of vascular disease and for modulating inflammatory and immune processes by using methylene chloride as a carbon monoxide generating compound.
WO 02/092075 and WO 2004/045598, which originate from some of the present inventors, disclose metal carbonyls that are carbon monoxide releasing compounds (CORMs) for the therapeutic delivery of CO to an in vivo or an ex vivo physiological target site. Some of the transition metal carbonyl compounds disclosed in these publications are soluble in water, which is desirable for formulating a pharmaceutical composition. Not all of the compounds disclosed in these publications, such as the cyclopentadienyl iron-carbonyl compound [CpFe(CO)3]PF6, were found to be soluble in water. This particular compound was soluble in dimethylsulphoxide (DMSO) and produced a precipitate during release of CO. Formation of a precipitate in biological system, whether before or after CO delivery to a physiological target, is undesirable and may be toxic to the organism or result in harmful physiological side effects.
WO 98/029115 (University of British Columbia) discloses transition metal nitrosyl complexes for treating hypertension, angina pectoris and congestive heart disease. The compounds disclosed in this publication require the presence of at least one nitrosyl ligand coordinated to the metal. Cyclopentadienyl metal carbonyl compounds of the form CpM(CO)2NO and Cp*M(CO)2NO, where M=Cr, Mo, W; Cp is a cyclopentadienyl ligand and Cp* is a pentamethyl cyclopentadienyl ligand, are exemplified in this document.
US 2004/0116448 (Schmalz, H.-G. et al) discloses the use of iron carbonyl complexes for the treatment of diseases caused by highly proliferating cells, such as tumour cells. The active compounds contain a butadiene moiety, which is bound to an iron tricarbonyl unit in an η4 manner. The butadiene moiety may form part of a five membered cyclic ring. Generation of a cyclopentadienyl group and its subsequent coordination to the transition metal in an η5 manner is not disclosed.
WO 03/066067 (Haas, W. et al) proposes as a class of compounds “CO containing organometallic complexes” for use in the treatment and/or prevention of diseases. Generic examples of organometallic transition metal-carbonyl compounds that fall within this class are described. Amongst these examples, the generic formulae for the following organometallic compounds are given:[(η5-CpR)M(CO)3] for M=Mn, Re;[(η5-CpR)M(CO)2] for M=Co, Rh;[(η5-CpR)M(CO)2X] for M=Fe, Ru;[(η5-CpR)M(CO)3X] for M=Cr, Mo, W;[η5-IndM(CO)2X] for M=Fe, Ru;[η5-IndM(CO)3X] for M=Cr, Mo, W;[(η5-CpR)M(CO)2L]+Y− for M=Fe, Ru; and[(η5-CpR)M(CO)3L]+Y− for Cr, Mo, W;where Cp is a cyclopentadienyl ligand, Ind is an indenyl ligand, R is H, alkyl, acyl, formyl, carboxylate, sugar, peptide or halide, X is alkyl, aryl, halide, OR′, SR′, O2CR′, S2CNR′2, S2P(OR′)2, L is CO, olefin, alkyne, or a monodentate 2 electron donor of O, S, N or P, and Y is a halide or a weakly coordinating anion.
Attaching a carboxylic derivative to the cyclopentadienyl ring is also proposed in order to modify biological compatibility and solubility. The following Mn complex is given as an example of a possible modified compound:
where R(X) is H, alkyl, aryl, formyl, acyl, carboxylate or fused C6 aromatic ring (indenyl ligand), and R′ is H, alkyl, peptide or sugar.
WO 03/066067 (Haas, W. et al) does not describe the synthesis of any of the above compounds and does not contain any literature reference to a procedure for their preparation. It is further noted that there is no evidence in this document, such as biological test data, in support of the use of these compounds for the delivery of CO in vivo or ex vivo.